Cr(VI) induces cytotoxicity in vitro through activation of ROS-mediated endoplasmic reticulum stress and mitochondrial dysfunction via the PI3K/Akt signaling pathway

Zhang, Yujing; Xiao, Fang; Liu, Xinmin; Liu, Kaihua; Zhou, Xiangyang; Zhong, Caigao

doi:10.1016/j.tiv.2017.03.003

Cited by 55 publications

(23 citation statements)

References 41 publications

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“…also resulting from ROS production (Sun et al, 2012). An S phase cell cycle delay was also found in L-02 hepatocytes upon exposure to Cr(VI) along with an increase in ROS production that may account for inhibition of the PI3K/Akt pathway leading to endoplasmic reticulum stress and mitochondrial dysfunction, which consequently induces apoptosis (Zhang et al, 2017). It was also shown that Cr(VI) reduction and ROS generation induced DNA oxidative damage (8-OHdG) and…”

Section: Discussionmentioning

confidence: 94%

“…In the same way, Cr(VI) exposure in human colorectal adenocarcinoma cells (DLD1 cell line) induced cell cycle delay at the S phase, also resulting from ROS production (Sun et al, ). An S phase cell cycle delay was also found in L‐02 hepatocytes upon exposure to Cr(VI) along with an increase in ROS production that may account for inhibition of the PI3K/Akt pathway leading to endoplasmic reticulum stress and mitochondrial dysfunction, which consequently induces apoptosis (Zhang et al, ). It was also shown that Cr(VI) reduction and ROS generation induced DNA oxidative damage (8‐OHdG) and increased γ‐H2AX, a sensitive indicator of DNA DSB, in Caco‐2 cells (Thompson et al, ).…”

Section: Discussionmentioning

confidence: 99%

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Cr(VI)‐induced genotoxicity and cell cycle arrest in human osteoblast cell line MG‐63

Monteiro

Santos

Bastos

et al. 2019

J of Applied Toxicology

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Occupational environments are major exposure routes to Cr(VI). However, Cr(VI) may also establish in bone tissues by ingestion or through Cr containing orthopaedic prostheses that, due to wear and corrosion, may release metal particles and ions potentially affecting bone tissue. The aim of this work was to evaluate the effects of clinically relevant concentrations of Cr(VI) in human osteoblasts, by integrating genotoxic effects, evaluated by the comet assay and cytokinesis‐blocked micronucleus assay (scoring the presence of micronucleus, nucleoplasmic bridges and nuclear division index), with the effects on cell cycle and cell viability. Human osteoblasts MG‐63 were in vitro exposed to Cr(VI) at concentrations ranging from 0.1 to 5 μm, for 24 and 48 hours. Results pointed out to a decrease of cell viability for both time exposures in a time‐ and dose‐dependent manner, which was related to cell cycle arrest and DNA damage. Chromosome abnormalities were also observed. Hence, these data suggest that cells arrested in the cell division with DNA damage may have followed cell death pathways, while some surviving ones still revealed DNA damage at chromosome level indicating abnormal cell division progression. In conclusion, Cr(VI) induced cytotoxic and genotoxic effects in human bone cells at concentrations that could be found in patients with metal‐on‐metal prostheses. In addition, the early onset of genotoxic damage induced by Cr(VI) at low concentrations after 24 hours of cell exposure alert to the relevance of periodic monitoring of patients for genotoxicity diagnosis after implantation of prostheses before clinical symptoms appear.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Cr(VI)‐induced genotoxicity and cell cycle arrest in human osteoblast cell line MG‐63

Monteiro

Santos

Bastos

et al. 2019

J of Applied Toxicology

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“…An increased production of oxidizing species by mammal cells as well as other eukaryotic cell models is highly correlated with mitochondrial dysfunction and apoptosis. 30 − 34 …”

Section: Resultsmentioning

confidence: 99%

Preferential Mitochondrial Localization of a Goniothalamin Fluorescent Derivative

et al. 2017

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A fluorescent 2,1,3-benzothiadiazole-containing goniothalamin derivative, BTD−GTN (1), has been synthesized and successfully tested in bioimaging experiments in live cells. The fluorescent compound proved to be capable of transposing the cell membranes, indicating its subcellular localization. The use of the benzothiadiazole core as the fluorophore revealed the favored localization of the GTN analogue 1 in the cytoplasm of live cells, preferentially in the mitochondria, in line with previous results that indicated the loss of mitochondrial transmembrane potential upon treatment with GTN. The results described herein highlight the potential of the BTD–GTN hybrid structures for future studies regarding the cellular mechanism of action of this family of compounds.

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“…The dark and light colours indicate the compounds with and without publications, respectively. www.nature.com/scientificreports/ ER stress markers 15,16 , were quantified using quantitative polymerase chain reaction (qPCR, Fig. 3b).…”

Section: Induction Of Er Stress In Mcf7 Cells By Test Compoundsmentioning

confidence: 99%

Decomposition profile data analysis of multiple drug effects identifies endoplasmic reticulum stress-inducing ability as an unrecognized factor

Morita

Mizuno

Kusuhara

2020

Sci Rep

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Chemicals have multiple effects in biological systems. Because their on-target effects dominate the output, their off-target effects are often overlooked and can sometimes cause dangerous adverse events. Recently, we developed a novel decomposition profile data analysis method, orthogonal linear separation analysis (OLSA), to analyse multiple effects. In this study, we tested whether OLSA identified the ability of drugs to induce endoplasmic reticulum (ER) stress as a previously unrecognized factor. After analysing the transcriptome profiles of MCF7 cells treated with different chemicals, we focused on a vector characterized by well-known ER stress inducers, such as ciclosporin A. We selected five drugs predicted to be unrecognized ER stress inducers, based on their inducing ability scores derived from OLSA. These drugs actually induced X-box binding protein 1 splicing, an indicator of ER stress, in MCF7 cells in a concentration-dependent manner. Two structurally different representatives of the five test compounds exhibited similar results in HepG2 and HuH7 cells, but not in PXB primary hepatocytes derived from human-liver chimeric mice. These results indicate that our decomposition strategy using OLSA uncovered the ER stress-inducing ability of drugs as an unrecognized effect, the manifestation of which depended on the background of the cells. Small compounds have the capacity to interact with multiple cellular proteins, thereby mediating multiple effects depending on their exposure to interacting proteins. It is quite difficult to identify the full range of effects of a new chemical, even for its developers, and some factors may be unrecognized. Even approved drugs show off-target effects that are often unrecognized during drug development, and which can lead to adverse reactions including lethal effects. For instance, astemizole has been withdrawn from the market in most countries because it causes a fatal side effect, cardiac arrhythmia 1,2 , by blocking the human Ether-ago go Related Gene potassium channel, thereby causing QT interval prolongation and torsade de pointes. However, we should not be too negative about unrecognized effects of small compounds, because identification of these can lead to drug repurposing. For example, memantine was synthesized in 1968 as a derivative of amantadine, an anti-influenza agent. Recently, it was revealed that this anti-influenza agent is also an antagonist for the N-methyl-D-aspartate receptor, and the drug has become a medication for dementia 3. Thus, the important question is how such unrecognized effects of chemicals can be identified. Profile data analysis is quite useful in addressing this issue. Although the terminology sometimes varies between contexts, the method is a type of multivariate analysis that describes data using multiple variables and investigates the relationship between data with high robustness and detection power by sharing information about the structure of the data 4. Data from "omics" analysis, which converts biological information of a specim...

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Cr(VI) induces cytotoxicity in vitro through activation of ROS-mediated endoplasmic reticulum stress and mitochondrial dysfunction via the PI3K/Akt signaling pathway

Cited by 55 publications

References 41 publications

Cr(VI)‐induced genotoxicity and cell cycle arrest in human osteoblast cell line MG‐63

Cr(VI)‐induced genotoxicity and cell cycle arrest in human osteoblast cell line MG‐63

Preferential Mitochondrial Localization of a Goniothalamin Fluorescent Derivative

Decomposition profile data analysis of multiple drug effects identifies endoplasmic reticulum stress-inducing ability as an unrecognized factor

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